Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelia homeostasis. The precise molecular mediators remain to be identified. In a mouse model in which the Tgfbr2 gene in stromal fibroblasts was inactivated, we found that stromal deletion of Tgfbr2 resulted in genetic and epigenetic changes in the adjacent epithelia including a loss of the cyclin dependent kinase (CDK) inhibitors p15 and p16. In addition, there was increased methylation at the p53-binding site of the p21 promoter region in the tumor cells. The mechanisms mediating the crosstalk between the epithelia and the stroma involved COX-2-mediated inflammation. Our studies demonstrate that attenuation of stromal TGFb signaling induces inflammation that, in turn, causes DNA damage as well as epigenetic and genetic alterations in epithelia. Therefore, therapeutic targeting of inflammation and the tumor microenvironment may be useful in treating cancers with downregulation of TGFb signaling in the stroma. Wa are currently investigating how these findings affect cancer metastatic process.